Lung nontumor
Other nonneoplastic disease

Topic Completed: 1 September 2017

Minor changes: 4 July 2020

Revised: 28 August 2018, last major update September 2017

Copyright: (c) 2003-2018,, Inc.

PubMed search: (Acute respiratory distress syndrome) ARDS (diffuse alveolar damage) DAD

Related topics: Acute fibrinous and organizing pneumonia

Akira Yoshikawa, M.D.
Andrey Bychkov, M.D., Ph.D.
Page views in 2019: 14,375
Page views in 2020 to date: 12,116
Cite this page: Yoshikawa, A. and Fukuoka, J. ARDS / DAD. website. Accessed August 3rd, 2020.
Definition / general
  • In 1994, the American European Consensus Conference (AECC) defined acute respiratory distress syndrome (ARDS) as "the acute onset of hypoxemia with bilateral infiltrates on frontal chest radiograph, with no evidence of left atrial hypertension" (AECC definition, Am J Respir Crit Care Med 1994;149:818)
  • In 2012, the ARDS Task Force revised the definition (Berlin definition, JAMA 2012;307:2526)
  • Diffuse alveolar damage (DAD) is manifested by injury to alveolar lining and endothelial cells, pulmonary edema, hyaline membrane formation and later by proliferative changes involving alveolar and bronchiolar lining cells and interstitial cells (Am J Pathol 1976;85:209)
Essential features
  • Acute and rapidly progressive hypoxia with bilateral pulmonary edema due to alveolar injury caused by pulmonary or systemic insults
  • 40% die within 28 days from onset of ARDS, mainly due to septic shock and multiple organ dysfunction syndrome (MODS)
  • DAD is the most common morphological pattern of ARDS; however the clinical syndrome of ARDS is not synonymous with the pathologic diagnosis of DAD
  • DAD pattern is often characterized by hyaline membranes in acute phase but shows a wide variety of findings that makes the diagnosis challenging
  • Previously known as "adult respiratory distress syndrome"
  • "Acute lung injury," an overlapping entity suggested in AECC definition, was removed from Berlin definition; the AECC definition of "acute lung injury non-ARDS" is compatible with Berlin definition of mild ARDS (JAMA 2012;307:2526)
ICD coding
  • Acute respiratory distress syndrome: J80
  • Bilateral lung without upper or lower predominance
  • Pathogenesis (N Engl J Med 2000;342:1334, Lancet 2016;388:2416):
    • Exudative (acute) phase: 1 - 7 days
      • Neutrophil mediated inflammation damages the alveolar capillary barrier (alveolar epithelium and endothelium), increases its permeability and causes intra-alveolar hemorrhage and edema
      • Protein rich edema interacts with alveolar surfactants, resulting in decreased pulmonary compliance
      • Hyaline membranes are developed on alveolar wall where epithelium is denudated and disrupted
    • Proliferative / organizing (subacute) phase: 1 - 3 weeks
      • Restoration of type II pneumocytes and subsequent differentiation into type I pneumocytes
      • Proliferation of myofibroblasts
      • Drainage of alveolar edema by restored type II pneumocytes
    • Fibrotic (chronic) phase: after 3 weeks
      • Collagenous fibrosis in alveolar spaces and interstitium
      • Refractory rigidity of alveoli due to architectural remodeling
  • Pathophysiology of hypoxia
    • Collapse of alveoli
    • Increased right to left intrapulmonary shunt
    • Decreased pulmonary compliance
      • Surfactant malfunction
      • Fibrosis
    • Decreased diffusing capacity due to pulmonary edema
    • Increased ventilation perfusion mismatch
    • Increased pulmonary vascular resistance
  • Mechanism of ARDS to cause MODS is not clear
  • Causes of pulmonary and extrapulmonary origin (see table below, N Engl J Med 2000;342:1334)
    • Infection
      • Bacteria: Mycoplasma, Mycobacteria, Legionella, Rickettsia
      • Virus: influenza virus, herpes virus, cytomegalovirus, hantavirus
      • Fungi: Pneumocystis jirovecii
    • Drug
      • Chemotherapeutic drugs: methotrexate, bleomycin, azathioprine, busulfan
      • Molecular targeted drugs
      • Gold
      • Amiodarone
      • Penicillamine
      • Nitrofurantoin
    • Autoimmune disease
    • Inhalation
      • Smoke
      • Sulfur dioxide
      • Oxygen
      • Nitrogen dioxide
Diagrams / tables

Causes of pulmonary and extrapulmonary origin
Direct lung injury Indirect lung injury
  • Common causes
    • Infectious pneumonia
    • Aspiration of gastric contents
  • Common causes
    • Sepsis
    • Severe trauma or burn, especially
        with shock and multiple transfusions
  • Less common causes
    • Pulmonary contusion
    • Fat emboli
    • Near drowning
    • Inhalational injury (particle, gas)
    • Reperfusion pulmonary edema, after
        lung transplantation or pulmonary embolectomy
  • Less common causes
    • Cardiopulmonary bypass
    • Drug
    • Acute pancreatitis
    • Autoimmune disease
    • Transfusion related acute lung injury

Images hosted on other servers:

Normal and acute phase

Proliferative / organizing phase

Clinical features
  • Acute and progressive respiratory failure
    • Usually starts 12 - 48 hours after the initial insult
    • Shortness of breath; dyspnea on exertion followed by dyspnea at rest
    • Hypoxia; PaO2/FIO2 ≤ 300 mm Hg
  • Often sepsis and MODS (JAMA 2016;315:788)
  • Respiratory dysfunction and physical disability may persist for months after remission of ARDS, with gradual improvement (N Engl J Med 2003;348:683)
  • Diagnosis of ARDS is based on clinical manifestation and its severity is evaluated with ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FIO2)
  • Berlin definition (JAMA 2012;307:2526)
    • Timing
      • Within 1 week of a known clinical insult or new or worsening respiratory symptoms
    • Chest imaging
      • Assessed by chest radiograph or computed tomography
      • Bilateral opacities, not fully explained by effusions, lobar / lung collapse or nodules
    • Origin of edema
      • Respiratory failure not fully explained by cardiac failure or fluid overload
      • Need objective assessment (e.g. echocardiography) to exclude hydrostatic edema if no risk factor present
    • Oxygenation (with positive end expiratory pressure [PEEP] or continuous airway pressure [CPAP] ≥ 5 cm H2O)
      • Mild: 200 < PaO2/FIO2 ≤ 300 mm Hg
      • Moderate: 100 < PaO2/FIO2 ≤ 200 mm Hg
      • Severe: PaO2/FIO2 ≤ 100 mm Hg
  • Lung biopsy can be helpful for critical care and prognosis estimation for patients with ARDS
    • Open lung biopsy provided a specific diagnosis for 84% of ARDS patients and an alternative treatment for 73% cases (Ann Thorac Surg 2014;98:1254)
    • ARDS with DAD has poorer prognosis (see prognostic factors)
    • Carefully consider biopsy if there is a high prediction for beneficial result and the risk of empirical therapy is not suitable or unsuccessful (Chest 2015;148:1073)
  • Arterial blood gas test
    • Hypoxemia
    • Ratio of pulse oximetric oxygen saturation to FIO2 (SpO2/FIO2) may be helpful for diagnosis and follow up (Chest 2007;132:410)
      • SpO2/FIO2 of 235 ≈ PaO2/FIO2 of 200 (sensitivity: 85%, specificity: 85%)
      • SpO2/FIO2 of 315 ≈ PaO2/FIO2 of 300 (sensitivity: 91%, specificity: 56%)
  • Other blood tests
    • Increased C reactive protein
    • Increased procalcitonin in septic ARDS
    • Increased ferritin (Am J Respir Crit Care Med 1999;159:1506)
    • Increased KL-6
    • Brain natriuretic peptide (BNP) test may helpful to distinguish ARDS and cardiogenic pulmonary edema (Chest 2007;131:964)
      • BNP ≤ 200 pg/ml is suggestive for ARDS (sensitivity: 40%, specificity: 91%)
      • BNP ≥ 1200 pg/ml is suggestive for cardiogenic pulmonary edema (sensitivity: 52%, specificity: 92%)
Radiology description
  • General
    • Heterogeneous bilateral shadows due to pulmonary edema
    • Must rule out atelectasis, pleural effusion and mass
    • Takes 12 - 24 hours from onset to be apparent
  • Chest radiograph
    • Exudative phase: ground glass opacity and consolidation with air bronchogram
    • Proliferative / organizing and fibrotic phases: reticular shadow and volume reduction
  • Chest CT
    • Exudative phase
      • Patchy to diffuse ground glass opacity with / without interlobular septal thickening
      • Dorsal consolidation due to infiltrate
    • Proliferative / organizing phase
      • Ground glass opacity with bronchiolectasis and bronchiectasis
      • Volume reduction
    • Fibrotic phase
      • Septal thickening and reticular shadow in ground glass opacity
      • Peripheral cystic and honeycomb-like lesion due to fibrosis
Prognostic factors
Case reports
  • Treatment for the original insult
  • Oxygen therapy for respiratory failure (Lancet 2016;388:2416)
    • Mechanical ventilation
      • PEEP or CPAP ≥ 5 cm H2O
      • With / without neuromuscular blockade, prone position and ECMO
  • Supportive care
    • Fluid management
    • Pharmacotherapy
      • Glucocorticoid
      • Anticoagulant
Clinical images

Images hosted on other servers:

Chest radiograph

Exudative phase

Changes in ARDS

Chest CT

Exudative phase

Proliferative / organizing phase

Fibrotic phase

Changes in ARDS

Gross description
  • Dark blue lungs with dots of hemorrhage on pleural surface
  • Heavy and firm due to edema and fibrosis
Gross images

Images hosted on other servers:

Collection of Dr. Yale Rosen

DAD images

Congestive phase

Microscopic (histologic) description
  • Exudative phase
    • Alveolar change (Am J Pathol 1976;85:209)
      • Hyaline membranes on alveolar duct or sacs
      • Interstitial and intra-alveolar edema
      • Collapsed alveoli
    • Epithelial change
      • Denudation and necrosis of type I pneumocytes
    • Vascular change
      • Necrosis of endothelial cells
      • Neutrophil aggregation
      • Micro thromboembolism
      • Hemorrhage
  • Proliferative / organizing phase (Arch Pathol Lab Med 2010;134:719)
    • Alveolar change
      • Organizing or remnants of hyaline membrane
      • Interstitial and intra-alveolar proliferation of fibroblasts / myofibroblasts
      • Lymphocytic infiltration
    • Epithelial change
      • Proliferation of type II pneumocyte
    • Vascular change
      • Endothelial injury and thromboembolism in arteries / arterioles
  • Fibrosis phase (Clin Chest Med 2000;21:435)
    • Alveolar change
      • Diffuse collagenous fibrosis
      • Microscopic honeycomb-like change
      • Traction bronchiolectasis
    • Epithelial change
      • Squamous cell hyperplasia
    • Vascular change (N Engl J Med 2000;342:1334)
      • Remodeling of arteries
      • Fibrosis in intima
      • Thickening of media
  • Others
    • May have superimposed pneumonia
    • Fibrin deposition
    • Organizing pneumonia; aggregated fibroblasts with bluish extracellular matrix
      • DAD with prominent organizing pneumonia is also called "organizing DAD"
Microscopic (histologic) images

Scroll to see all images:

Images hosted on PathOut server:

Contributed by Akira Yoshikawa

Case 1: DAD of proliferative / organizing to fibrotic phase
Clinical manifestation: ARDS; dermatological manifestations such as mechanic hands, Gottron papules and photosensitivity; positivity for serum anti MDA5 antibody

Biopsy from S5

Biopsy from S9

Case 2: DAD of fibrotic phase; hard to rule out acute exacerbation of IPF
Clinical manifestation: acute respiratory failure (ARDS?); history of frequent fever; antinuclear antibody (80x)

Biopsy No. 1

Biopsy No. 2

Case 3: Organizing DAD
Clinical manifestation: ARDS; mechanic hands, Raynaud phenomenon, nailfold capillary change; negative for autoimmune antibodies

Biopsy from S5

Images hosted on other servers:

DAD in exudative and proliferative / organizing phase

Collapsed alveoli

Immature lung

Exudative phase

Hyaline membranes

Proliferative / organizing phase

Fibroblastic proliferation with remnants of hyaline membranes

Type II pneumocyte hyperplasia

Organizing DAD

Collection of Dr. Yale Rosen

Exudative phase

Hyaline membrane

Hyaline membrane and deposition of fibrin

Proliferative / organizing phase

Fibroblastic proliferation with remnants of hyaline membrane

Type II
hyperplasia and
hyaline membrane


Cytology description
  • Bronchoalveolar lavage (BAL) fluid
    • Increased neutrophils in ARDS
    • Helpful for the diagnosis of underlying disease
Positive stains
Electron microscopy description
  • Changes in epithelium, endothelium and interstitium can be seen (N Engl J Med 2000;342:1334)
    • Exudative phase
      • Vacuolization in damaged endothelial cells
      • Replacement of epithelial cells by hyaline membrane on the basement membrane
    • Proliferative / organizing and fibrotic phases
      • Re-epithelialization of type II pneumocytes with microvilli and lamellar bodies with surfactant
      • Flattening of cytoplasm and loss of lamellar bodies and microvilli of type II pneumocyte, indicating transformation to type I pneumocyte
      • Collagen deposition

Histology of DAD

Differential diagnosis
Board review style question #1
Which of the following findings is most suggestive for ARDS / DAD?

  1. Bacterial pneumonia
  2. Diffuse collagenous fibrosis
  3. Hyaline membranes
  4. Onset of respiratory failure 1 week after cardiac surgery
  5. Organizing pneumonia
Board review answer #1
C. Hyaline membranes
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